Piperidine-substituted Mnk inhibitors and methods related thereto

ABSTRACT

The present invention relates to compounds according to Formula (I):or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein X1, X2, R1, R2, R3 and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula (I) compounds as well as methods for utilizing the compounds of Formula (I) and the pharmaceutically acceptable compositions of Formula (I) compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/233,507, filed Dec. 27, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/895,523, filed Feb. 13, 2018, which claims thebenefit of U.S. Provisional Patent Application No. 62/458,671, filedFeb. 14, 2017, the contents of which are herein incorporated byreference in their entirety.

FIELD

The present invention generally relates to compounds having activity asinhibitors of MAP kinase interacting kinase (Mnk), as well as to relatedcompositions and methods containing or utilizing the same. Suchcompounds find utility in any number of therapeutic applications,including the treatment of cancer.

BACKGROUND

Eukaryotic initiation factor 4E (eIF4E) is a general translation factor,but it has the potential to enhance preferentially the translation ofmessenger RNAs (mRNAs) that lead to production of malignancy-associatedproteins. This selectivity may relate to an increased requirement foreIF4E and its binding partners for the translation of mRNAs containingextensive secondary structure in their 5′-untranslated regions(5′-UTRs). These mRNAs include those encoding certain proteins thatcontrol cell cycle progression and tumorigenesis. Under normal cellularconditions the translation of these malignancy-associated mRNAs issuppressed as the availability of active eIF4E is limited; however,their levels can increase when eIF4E is over-expressed orhyperactivated. Elevated levels of eIF4E have been found in many typesof tumors and cancer cell lines including cancers of the colon, breast,bladder, lung, prostate, gastrointestinal tract, head and neck,Hodgkin's lymphomas and neuroblastomas.

Initiation of cap-dependent translation is thought to depend on theassembly of eIF4F, an initiation factor complex including eIF4E, thescaffold protein eIF4G, and the RNA helicase eIF4A. Because eIF4E is theonly one of these proteins that binds directly to the mRNA capstructure, it is the key factor for the assembly of eIF4F at the 5′ cap.The scaffold protein, eIF4G, also recruits the 40S ribosomal subunit tothe mRNA via its interaction with eIF3 and binds eIF4B, a protein thataids the RNA-helicase function of eIF4A, thus facilitating thetranslation of mRNAs that contain structured 5′-UTRs. The availabilityof eIF4E as part of the eIF4F complex is a limiting factor incontrolling the rate of translation, and therefore eIF4E is an importantregulator of mRNA translation.

Regulation of eIF4E activity forms a node of convergence of thePI3K/Akt/mTOR and Ras/Raf/MAPK signaling pathways. The PI3K(phosphoinositide 3-kinase)/PTEN (phosphatase and tensin homologuedeleted on chromosome ten)/Akt/mTOR (mammalian target of rapamycin)pathway is often involved in tumorgenesis and in sensitivity andresistance to cancer therapy. Deregulated signaling through thePI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations incritical components of this pathway and/or mutations at upstream growthfactor receptors or signaling components. PI3K initiates a cascade ofevents when activated by, for example, extracellular growth factors,mitogens, cytokines and/or receptors, PDK1 activates Akt, which in turnphosphorylates and inactivates the tumor suppressor complex comprisingTSC1 and 2 (tuberous sclerosis complex 1/2), resulting in the activationof mTORC1 (target of rapamycin complex 1) by Rheb-GTP. Activation ofPDK1 and Akt by PI3Ks is negatively regulated by PTEN.

PTEN is a critical tumor suppressor gene and is often mutated orsilenced in human cancers. Its loss results in activation of Akt andincreases downstream mTORC1 signaling. The involvement of mTOR complex1(mTORC1) in neoplastic transformation appears to depend on itsregulatory role toward the eIF4F complex; overexpression of eIF4E canconfer resistance to rapamycin. mTORC1 regulates the eIF4F complexassembly that is critical for the translation of mRNAs associated withcell growth, prevention of apoptosis and transformation. mTORC1 achievesthis by phosphorylation and inactivation of 4E-BPs and the subsequentdissociation of 4E-BPs from eIF4E. This then enables eIF4E to interactwith the scaffold protein eIF4G, permitting assembly of the eIF4Fcomplex for the translation of structured mRNAs. mTORC1 also promotesactivation of the translational activator, S6K, which phosphorylates theribosomal protein S6 and other substrates, including eIF4B. mTORC1signaling is inhibited by rapamycin and its analogues (rapalogs),although these compounds act allosterically, rather than directlyinhibiting mTOR kinase activity.

Given the importance of the PI3K/Akt/mTOR pathway in regulating mRNAtranslation of genes that encode for pro-oncogenic proteins andactivated mTORC1 signaling in a high proportion of cancers, thesekinases have been actively pursued as oncology drug targets. A number ofpharmacological inhibitors have been identified, some of which havereached advanced clinical stages. However, it has recently become clearthat the mTOR pathway participates in a complicated feedback loop thatcan impair activation of Akt. It has been shown that prolonged treatmentof cancer cells or patients with mTOR inhibitors causes elevated PI3Kactivity that leads to phosphorylation of Akt and eIF4E, and promotescancer cell survival. eIF4E, acting downstream of Akt and mTOR,recapitulates Akt's action in tumorigenesis and drug resistance, and Aktsignaling via eIF4E is an important mechanism of oncogenesis and drugresistance in vivo.

In addition to the PI3K/Akt/mTOR pathway, eIF4E is also the target ofthe Ras/Raf/MAP signaling cascade which is activated by growth factorsand for the stress-activated p38 MAP kinase pathway. Erk1/2 and p38 thenphosphorylate MAP kinase-interacting kinase 1 (Mnk1) and MAPkinase-interacting kinase 2 (Mnk2). The Erk pathway is also activated inmany cancers, reflecting, for example, activating mutations in Ras(found in around 20% of tumors) or loss of function of the RasGTPase-activator protein NF 1. Mnk1 and Mnk2 are threonine/serineprotein kinases and specifically phosphorylate serine 209 (Ser209) ofeIF4E within the eIF4F complex, by virtue of the interaction betweeneIF4E and the Mnks, which serves to recruit Mnks to act on eIF4E. Micewith mutated eIF4E, in which Ser209 is replaced by alanine, show noeIF4E phosphorylation and significantly attenuated tumor growth.Significantly, while Mnk activity is necessary for eIF4E-mediatedoncogenic transformation, it is dispensable for normal development.Pharmacologically inhibiting Mnks thus presents an attractivetherapeutic strategy for cancer.

Despite increased understanding of Mnk structure and function, littleprogress has been made with regard to the discovery of pharmacologicalMnk inhibitors and relatively few Mnk inhibitors have been reported:CGP052088 (Tschopp et al., Mol Cell Biol Res Commun. 3(4):205-211,2000); CGP57380 (Rowlett et al., Am J Physiol Gastrointest LiverPhysiol. 294(2):G452-459, 2008); and Cercosporamide (Konicek et al.,Cancer Res. 71(5):1849-1857, 2011). These compounds, however, havemainly been used for the purpose of Mnk target validation. Morerecently, investigators have proposed further compounds for treatingdiseases influenced by the inhibition of kinase activity of Mnk1 and/orMnk2, including, for example, the compounds disclosed in InternationalPatent Application Publication WO 2014/044691 and the various patentdocuments cited therein, the4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3,-d]pyrimidinesdisclosed by Yu et al., European Journal of Med. Chem., 95: 116-126,2015, and the6′-(6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dioneand the various compounds disclosed in International Patent ApplicationPublication WO 2015/200481.

Accordingly, while advances have been made in this field there remains asignificant need in the art for compounds having improved solubilitywhile retaining the potency to specifically inhibit Mnk and otherreceptor activity. The present invention fulfills this need and providesfurther related advantages.

SUMMARY

The present invention is directed to compounds that inhibit or modulatethe activity of Mnk, as well as stereoisomers, tautomers andpharmaceutically acceptable salts of such compounds as candidatetherapeutic agents. The present invention also is directed tocompositions containing such compounds and associated methods fortreating conditions that would benefit from Mnk inhibition, such ascancer.

In one embodiment, the invention is directed to compounds that conformto Formula (I) as well as to a stereoisomer, tautomer orpharmaceutically acceptable salt of such compounds:

wherein:X¹ is CH₂ and X² is NR² or X¹ is NR² and X² is CH₂;R¹ is H, (C₁-C₄)alkyl, halogen or cyano;R² is H, (C₁-C₈)alkyl or (C₁-C₈)haloalkyl;R³ is (C₁-C₈)alkyl, or R² and an adjacent R³, or R³ and an adjacent R³,together with the ring atoms to which they are attached, form a fusedfive- or six-membered heterocycle or cycloalkyl ring; andn is 0, 1, 2, 3 or 4;wherein alkyl, heterocycle and cycloalkyl are optionally substitutedwith OH, CN, NH₂, NO2, halogen, alkyl and alkoxy.

In another embodiment, compositions are disclosed comprising a compoundof structure (I) in combination with a pharmaceutically acceptablecarrier, diluent or excipient.

In a further embodiment, methods are provided for treating a Mnkdependent condition in a mammal in need thereof. Such methods compriseadministering an effective amount of a compound of structure (I), orcompositions comprising the same, to the mammal. Such conditionsinclude, but are not limited to, various forms of cancer as discussed inmore detail below.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Definitions

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

“Amino” refers to the —NH₂ substituent.

“Carboxyl” refers to the —CO2H substituent.

“Carbonyl” refers to a —C(O)— or —C(═O)— group. Both notations are usedinterchangeably within the specification.

“Cyano” refers to the —C≡N substituent.

“Acetyl” refers to the —C(O)CH₃ substituent.

“Hydroxy” or “hydroxyl” refers to the —OH substituent.

“Oxo” refers to an oxygen of —O— substituent.

The phrase “MAP kinase interacting kinase” or the term “Mnk” refers toall isoforms of the MAP kinase interacting kinase protein includingMnk-1 and Mnk-2.

“Alkyl” refers to a saturated, straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), from one to eight carbon atoms(C₁-C₈ alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and whichis attached to the rest of the molecule by a single bond. Exemplaryalkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like.

“Lower alkyl” has the same meaning as alkyl defined above but havingfrom one to four carbon atoms (C₁-C₄ alkyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon (alkyl) chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, respectively. Alkylenescan have from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single or double bond. The points ofattachment of the alkylene chain to the rest of the molecule can bethrough one carbon or any two carbons within the chain. “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl having the indicated number of carbon atoms as defined above.Examples of alkoxy groups include without limitation —O-methyl(methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy), —O— isopropyl (isopropoxy) and the like.

“Acyl” refers to a radical of the formula —C(O)R_(a) where R_(a) is analkyl having the indicated number of carbon atoms.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls arehydrocarbon ring system radical comprising hydrogen and 6 to 9 carbonatoms and at least one aromatic ring; hydrocarbon ring system radicalcomprising hydrogen and 9 to 12 carbon atoms and at least one aromaticring; hydrocarbon ring system radical comprising hydrogen and 12 to 15carbon atoms and at least one aromatic ring; or hydrocarbon ring systemradical comprising hydrogen and 15 to 18 carbon atoms and at least onearomatic ring. For purposes of this invention, the aryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. “Optionally substituted aryl” refers to an aryl group or asubstituted aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,three to nine carbon atoms, three to eight carbon atoms, three to sevencarbon atoms, three to six carbon atoms, three to five carbon atoms, aring with four carbon atoms, or a ring with three carbon atoms. Thecycloalkyl ring may be saturated or unsaturated and attached to the restof the molecule by a single bond. Monocyclic radicals include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo (bromine), chloro (chlorine), fluoro(fluorine), or iodo (iodine).

“Haloalkyl” refers to an alkyl radical having the indicated number ofcarbon atoms, as defined herein, wherein one or more hydrogen atoms ofthe alkyl group are substituted with a halogen (halo radicals), asdefined above. The halogen atoms can be the same or different. Exemplaryhaloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocyclyl”, heterocycle”, or “heterocyclic ring” refers to a stable3- to 18-membered saturated or unsaturated radical which consists of twoto twelve carbon atoms and from one to six heteroatoms, for example, oneto five heteroatoms, one to four heteroatoms, one to three heteroatoms,or one to two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Exemplary heterocycles include withoutlimitation stable 3-15 membered saturated or unsaturated radicals,stable 3-12 membered saturated or unsaturated radicals, stable 3-9membered saturated or unsaturated radicals, stable 8-membered saturatedor unsaturated radicals, stable 7-membered saturated or unsaturatedradicals, stable 6-membered saturated or unsaturated radicals, or stable5-membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of non-aromatic heterocyclyl radicals include, butare not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclylsinclude heteroaryls as defined herein, and examples of aromaticheterocyclyls are listed in the definition of heteroaryls below.

“Heteroaryl” or “heteroarylene” refers to a 5- to 14-membered ringsystem radical comprising hydrogen atoms, one to thirteen carbon atoms,one to six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a stable 5-12 membered ring, astable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8membered ring, a stable 5-7 membered ring, or a stable 6 membered ringthat comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. The heteroatom may be a member of an aromatic ornon-aromatic ring, provided at least one ring in the heteroaryl isaromatic. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl).

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated, “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

In this description, a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound of the invention. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease.

The term “effective amount” refers to an amount of a compound of theinvention or other active ingredient sufficient to provide a therapeuticor prophylactic benefit in the treatment or prevention of a disease orto delay or minimize symptoms associated with a disease. Further, atherapeutically effective amount with respect to a compound of theinvention means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with acompound of the invention, the term can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes ofdisease, or enhances the therapeutic efficacy or synergies with anothertherapeutic agent.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, MAP kinase interacting kinase (Mnk). “Modulation”, in itsvarious forms, is intended to encompass inhibition, antagonism, partialantagonism, activation, agonism and/or partial agonism of the activityassociated with Mnk. Mnk inhibitors are compounds that bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. The ability of a compound to modulate Mnk activity can bedemonstrated in an enzymatic assay or a cell-based assay.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug that is a compoundwhich upon administration to a patient must undergo chemical conversionby metabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds in accordance with Formula (I) areesters, acetamides, and amides.

Compounds of the Invention

The present invention is generally directed to compounds encompassed bythe genus of Formula (I) or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof.

In one embodiment X¹ is CH₂ and X² is NR². In another embodiment X¹ isNR² and X² is CH₂.

In one embodiment R¹ is H. In another embodiment R¹ is methyl. Inanother embodiment R¹ is Cl. In yet another embodiment leis cyano.

In one embodiment R² is H.

In one embodiment R² is methyl. In another embodiment R² is ethyl. Inanother embodiment R² is isopropyl. In another embodiment R² istert-butyl.

In one embodiment R² is 3,3,3-trifluoropropyl. In another embodiment R²is 2,2-difluoroethyl.

In another embodiment R² is methylcyclopropane.

In one embodiment R³ is H or methyl.

In one embodiment a compound according to Formula (I), or astereoisomer, tautomer or pharmaceutically acceptable salt thereof isselected from compounds 3D, 3K, 3L, 3X, 3Y, rac-1F, 1Fa, 1Fb, rac-2F,2Fa and 2Fb.

The inventive compounds according to Formula (I) may beisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of according to Formula (I) includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, or iodine. Illustrative of such isotopes are ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I,respectively. These radiolabelled compounds can be used to measure thebiodistribution, tissue concentration and the kinetics of transport andexcretion from biological tissues including a subject to which such alabelled compound is administered. Labeled compounds are also used todetermine therapeutic effectiveness, the site or mode of action, and thebinding affinity of a candidate therapeutic to a pharmacologicallyimportant target. Certain radioactive-labelled compounds according toFormula (I), therefore, are useful in drug and/or tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O an¹³N, provides labeled analogs of the inventive compounds that are usefulin Positron Emission Tomography (PET) studies, e.g., for examiningsubstrate receptor occupancy. Isotopically-labeled compounds accordingto Formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples section as set out belowusing an appropriate isotopic-labeling reagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds according toFormula (I). Such products may result from, for example, the oxidation,reduction, hydrolysis, amidation, esterification, and like processesprimarily due to enzymatic activity upon administration of a compound ofthe invention. Accordingly, the invention includes compounds that areproduced as by-products of enzymatic or non-enzymatic activity on aninventive compound following the administration of such a compound to amammal for a period of time sufficient to yield a metabolic product.Metabolic products, particularly pharmaceutically active metabolites aretypically identified by administering a radiolabelled compound of theinvention in a detectable dose to a subject, such as rat, mouse, guineapig, monkey, or human, for a sufficient period of time during whichmetabolism occurs, and isolating the metabolic products from urine,blood or other biological samples that are obtained from the subjectreceiving the radiolabelled compound.

The invention also provides pharmaceutically acceptable salt forms ofFormula (I) compounds. Encompassed within the scope of the invention areboth acid and base addition salts that are formed by contacting apharmaceutically suitable acid or a pharmaceutically suitable base witha compound of the invention.

To this end, a “pharmaceutically acceptable acid addition salt” refersto those salts which retain the biological effectiveness and propertiesof the free bases, which are not biologically or otherwise undesirable,and which are formed with inorganic acids such as, but are not limitedto, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

Similarly, a “pharmaceutically acceptable base addition salt” refers tothose salts which retain the biological effectiveness and properties ofthe free acids, which are not biologically or otherwise undesirable.These salts are prepared by addition of an inorganic base or an organicbase to the free acid. Salts derived from inorganic bases include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compounds of the invention may be truesolvates, while in other cases the compounds of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

Compounds of the invention, or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule. Non-limiting example of tautomersinclude enol/keto, lactam/lactim, amide/imidic and amine/imine forms.

Similar tautomers exist for Formula (I) compounds. The inventivecompounds are synthesized using conventional synthetic methods, and morespecifically using the general methods noted below. Specific syntheticprotocols for several compounds in accordance with the present inventionare described in the Examples.

Pharmaceutical Formulations

In one embodiment, a compound according to Formula (I) is formulated aspharmaceutically acceptable compositions that contain a Formula (I)compound in an amount effective to treat a particular disease orcondition of interest upon administration of the pharmaceuticalcomposition to a mammal. Pharmaceutical compositions in accordance withthe present invention can comprise a Formula (I) compound in combinationwith a pharmaceutically acceptable carrier, diluent or excipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfate; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

In certain embodiments a pharmaceutical composition comprising acompound of Formula I is administered to a mammal in an amountsufficient to inhibit Mnk activity upon administration, and preferablywith acceptable toxicity to the same. Mnk activity of Formula (I)compounds can be determined by one skilled in the art, for example, asdescribed in the Examples below. Appropriate concentrations and dosagescan be readily determined by one skilled in the art.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of a Mnk related condition or disease in the mammal,preferably a human. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the condition and its severity, the manner ofadministration, and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

Compounds of the invention, or pharmaceutically acceptable salt thereof,may also be administered simultaneously with, prior to, or afteradministration of one or more other therapeutic agents. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and theother active agent can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

In certain embodiments, the disclosed compounds are useful forinhibiting the activity of Mnk and/or can be useful in analyzing Mnksignaling activity in model systems and/or for preventing, treating, orameliorating a symptom associated with a disease, disorder, orpathological condition involving Mnk, preferably one afflicting humans.A compound which inhibits the activity of Mnk will be useful inpreventing, treating, ameliorating, or reducing the symptoms orprogression of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by Mnk, such as, for example, haematological tumors, solidtumors, and/or metastases thereof, including leukaemias andmyelodysplastic syndrome, malignant lymphomas, for example, B-celllymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin's lymphoma,non-Hodgin's lymphoma and Burkitt lymphoma, head and neck tumorsincluding brain tumors and brain metastases, tumors of the thoraxincluding non-small cell and small cell lung tumors, gastrointestinaltumors, endocrine tumors, mammary and other gynecological tumors,urological tumors including renal, bladder and prostate tumors, skintumors, and sarcomas, and/or metastases thereof.

Furthermore, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of cytokine related diseases, such as inflammatory diseases,allergies, or other conditions associated with proinflammatorycytokines. Exemplary inflammatory diseases include without limitation,chronic or acute inflammation, inflammation of the joints such aschronic inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; inflammatory skin diseases such assunburn, psoriasis, erythroderma psoriasis, pustular psoriasis, eczema,dermatitis, acute or chronic graft formation, atopic dermatitis, contactdermatitis, urticaria and scleroderma; inflammation of thegastrointestinal tract such as inflammatory bowel disease, Crohn'sdisease and related conditions, ulcerative colitis, colitis, anddiverticulitis; nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus and relateddisorders, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,respiratory diseases such as asthma, bronchitis, chronic obstructivepulmonary disease (COPD), inflammatory lung disease and adultrespiratory distress syndrome, and allergic rhinitis; endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from the group consisting of granulomatous thyroiditis,lymphocytic thyroiditis, invasive fibrous thyroiditis, acutethyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud'sphenomenon, Sjogren's syndrome, neuroinflammatory disease, sepsis,conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis,lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis,laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis,gingivitis. oesophagitis, gastritis, peritonitis, hepatitis,cholelithiasis, cholecystitis, glomerulonephritis, goodpasture'sdisease, crescentic glomerulonephritis, pancreatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Although inflammation is the unifying pathogenic process of thesediseases, current therapies only treat the symptoms of the disease andnot the underlying cause of inflammation. The compositions of thepresent invention are useful for the treatment and/or prophylaxis ofinflammatory diseases and related complications and disorders.

Accordingly, certain embodiments are directed to a method for treating aMnk dependent condition in a mammal in need thereof, the methodcomprising administering an effective amount of a pharmaceuticalcomposition as described above (i.e., a pharmaceutical compositioncomprising any one or more compounds of Formula (I)) to a mammal.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

-   -   (i) preventing the disease or condition from occurring in a        mammal, in particular, when such mammal is predisposed to the        condition but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease or condition, i.e., arresting its        development;    -   (iii) relieving the disease or condition, i.e., causing        regression of the disease or condition; or    -   (iv) relieving the symptoms resulting from the disease or        condition, i.e., relieving pain without addressing the        underlying disease or condition. As used herein, the terms        “disease” and “condition” may be used interchangeably or may be        different in that the particular malady or condition may not        have a known causative agent (so that etiology has not yet been        worked out) and it is therefore not yet recognized as a disease        but only as an undesirable condition or syndrome, wherein a more        or less specific set of symptoms have been identified by        clinicians.

As described above deregulation of protein synthesis is a common eventin human cancers. A key regulator of translational control is eIF4Ewhose activity is a key determinant of tumorigenicity. Becauseactivation of eIF4E involves phosphorylation of a key serine (Ser209)specifically by MAP kinase interacting kinases (Mnk), inhibitors of Mnkare suitable candidate therapeutics for treating cell proliferativedisorders such as cancer. A wide variety of cancers, including solidtumors, lymphomas and leukemias, are amenable to the compositions andmethods disclosed herein. Types of cancer that may be treated include,but are not limited to adenocarcinoma of the breast, prostate, andcolon; all forms of bronchogenic carcinoma of the lung; myeloid;melanoma; hepatoma; neuroblastoma; papilloma; apudoma; choristoma;branchioma; malignant carcinoid syndrome; carcinoid heart disease; andcarcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal,Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oatcell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell,and transitional cell). Additional types of cancers that may be treatedinclude histiocytic disorders; leukemia; histiocytosis malignant;Hodgkin's disease; immunoproliferative small; non-Hodgkin's lymphoma;diffuse large B cell lymphoma, T-cell lymphoma, B-cell lymphoma, hairycell lymphoma, Burkitt lymphoma, plasmacytoma; reticuloendotheliosis;melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma;fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma;mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma;craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma; mesonephroma;myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma;trophoblastic tumor.

Other cancers that can be treated using the inventive compounds includewithout limitation adenoma; cholangioma; cholesteatoma; cyclindroma;cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma;hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma;sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma;myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma;ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma;neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma;paraganglioma; paraganglioma nonchromaffin.

In one embodiment the inventive compounds are candidate therapeuticagents for the treatment of cancers such as angiokeratoma; angiolymphoidhyperplasia with eosinophilia; angioma sclerosing; angiomatosis;glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma;pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes;fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma;liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovariancarcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; andcervical dysplasia.

In a particular embodiment, the present disclosure provides methods fortreating solid tumor, colon cancer, rectal cancer, colorectal cancer,bladder cancer, gastric cancer, esophageal cancer, head and neck cancer,myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma,glioblastoma, hepatocellular cancers, hepatocellular carcinoma, thyroidcancer, lung cancer, non-small cell lung cancer, a hematological cancer,leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuselarge B cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,Burkitt lymphoma, pancreatic cancer, melanoma, myeloma, multiplemyeloma, pancreatic carcinoma, renal cell carcinoma, renal cancer,cervical cancer, urothelial cancer, prostate cancer,castration-resistant prostate cancer, ovarian cancer, breast cancer ortriple-negative breast cancer. According to such a method, atherapeutically effective amount of at least one compound according toFormula (I) or a stereoisomer, tautomer or pharmaceutically acceptablesalt thereof can be administered to a subject who has been diagnosedwith a cell proliferative disease, such as a cancer. Alternatively, apharmaceutical composition comprising at least one compound according toFormula (I) or a stereoisomer, tautomer or pharmaceutically acceptablesalt thereof can be administered to a subject who has been diagnosedwith cancer.

In certain embodiments, the compounds in accordance with the inventionare administered to a subject with cancer in conjunction with otherconventional cancer therapies such as radiation treatment or surgery.Radiation therapy is well-known in the art and includes X-ray therapies,such as gamma-irradiation, and radiopharmaceutical therapies.

In certain embodiments, the inventive Mnk inhibitor compounds are usedwith at least one anti-cancer agent. Anti-cancer agents includechemotherapeutic drugs. A chemotherapeutic agent includes, but is notlimited to, an inhibitor of chromatin function, a topoisomeraseinhibitor, a microtubule inhibiting drug, a DNA damaging agent, anantimetabolite (such as folate antagonists, pyrimidine analogs, purineanalogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNAinteractive agent (such as an intercalating agent), and a DNA repairinhibitor.

Illustrative chemotherapeutic agents include, without limitation, thefollowing groups: anti-metabolites/anti-cancer agents, such aspyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,gemcitabine and cytarabine) and purine analogs, folate antagonists andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (vinblastine,vincristine, and vinorelbine), microtubule disruptors such as taxane(paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilonesand navelbine, epidipodophyllotoxins (etoposide, teniposide), DNAdamaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide and etoposide (VP 16)); antibiotics such asdactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates—busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes—dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP470, genistein) and growth factorinhibitors (vascular endothelial growth factor (VEGF) inhibitors,fibroblast growth factor (FGF) inhibitors); angiotensin receptorblocker; nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); chimeric antigen receptors; cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan,irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin disruptors.

In certain embodiments, an Mnk inhibitor in accordance with the presentinvention is used simultaneously, in the same formulation or in separateformulations, or sequentially with an additional agent(s) as part of acombination therapy regimen.

Mnk inhibitors according to Formula (I) including their correspondingsalts and pharmaceutical compositions of Formula (I) compounds are alsoeffective as therapeutic agents for treating or preventing cytokinemediated disorders, such as inflammation in a patient, preferably in ahuman. In one embodiment, a compound or composition in accordance withthe invention is particularly useful for treating or preventing adisease selected from the group consisting of chronic or acuteinflammation, chronic inflammatory arthritis, rheumatoid arthritis,psoriasis, COPD, inflammatory bowel disease, septic shock, Crohn'sdisease, ulcerative colitis, multiple sclerosis and asthma.

In a further aspect of the invention, the inventive compounds orpharmaceutically acceptable formulations of the inventive compounds areprovided as inhibitors of Mnk activity. Such inhibition is achieved bycontacting a cell expressing Mnk with a compound or a pharmaceuticallyacceptable formulation, to lower or inhibit Mnk activity, to providetherapeutic efficacy for a Mnk dependent condition in a mammal in needthereof.

Therapeutically effective dosages of a compound according to Formula (I)or a composition of a Formula (I) compound will generally range fromabout 1 to 2000 mg/day, from about 10 to about 1000 mg/day, from about10 to about 500 mg/day, from about 10 to about 250 mg/day, from about 10to about 100 mg/day, or from about 10 to about 50 mg/day. Thetherapeutically effective dosages may be administered in one or multipledoses. It will be appreciated, however, that specific doses of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated, timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

General Synthetic Methods

Method 1:

Formation of intermediate IV, where X=halogen or other leaving group,such as —OTf, —OTs or —OMs, was accomplished by exposing compound II toa ketone III, or a ketone equivalent such as IIIa, IIIb or IIIc underacidic conditions. More specifically, exposing II where X is Cl or Br toa ketone III in 1,4-dioxane and concentrated sulfuric acid with heatingyields intermediate IV.

Formula I compounds were synthesized via Buchwald-Hartwig coupling,Ullmann-type coupling, or nucleophilic aromatic substitution. Thus,contacting intermediate IV where X=halogen or other leaving group, suchas —OTf, —OTs or —OMs, with a compound of Formula V or Va underconditions suitable for coupling, or nucleophilic aromatic substitutiongave Formula I or Ia compounds. Ia may be deprotected to yield I.

Method 2:

In an alternative method, the leaving group X of intermediate IV, whereX=halogen or other leaving group such as —OTf, —OTs or —OMs, may bedisplaced with an appropriate N nucleophile under conditions similar tothose described above for the synthesis of I so as to affordintermediate V or protected intermediate Va. Va may be deprotected toyield V.

Formula I or Ia compounds are readily synthesized by contactingintermediate V with a pyrimidine compound VI or VIa, 2 where X=halogenor other leaving group such as —OTf, —OTs or —OMs, under the conditionsof Buchwald-Hartwig coupling, Ullmann-type coupling, or nucleophilicaromatic substitution. Ia may be deprotected to yield I.

More specific synthetic methods for Formula I compounds are set forthbelow. It is understood that if protecting groups (“P”) are used duringthe synthesis of intermediates, or if a Formula I compound contains oneor more protecting groups, then such protecting groups are removed bymethods known in the chemical art.

It is also understood that R′, R² or R³ group of a Formula I compoundcan be furnished at a suitable stage of the synthesis via conventionalmethods known in the chemical art.

EXAMPLES

The following examples are provided for purpose of illustration and notlimitation.

Example 1:(R)-6-(6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 1Fa) and(S)-6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 1Fb)

Synthesis ofN-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxamide(3)

A suspension ofN-(6-amino-5-methylpyrimidin-4-yl)cyclopropanecarboxamide (1, 0.82 g,4.29 mmol),6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(2, 1.40 g, 4.29 mmol), and cesium carbonate (2.79 g, 8.58 mmol) in1,4-dioxane (20 mL) was purged with argon for 15 min. To this mixturewas added 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.12 g, 0.21mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.10 g,0.21 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.21 mmol)and palladium acetate (0.049 g, 0.21 mmol). The mixture was purged foranother 5 min and the vial was sealed. The reaction was stirred at 100°C. for 16 h. After completion, the reaction mass was diluted with 5%methanol in dichloromethane (150 mL) and passed through a bed of celite.The filtrate was concentrated and the crude was purified by combiflashcolumn chromatography using 3-5% methanol in dichloromethane to affordN-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxamide(3) as yellow solid. Yield: 0.96 g, 51%; MS (ESI) m/z 438.1 [M+1]⁺.

(R)-6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 1Fa) and(S)-6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 1Fb)

To a solution ofN-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-c]pyridine-3,3′-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxamide(3, 0.95 g, 2.17 mmol) in tetrahydrofuran, ethanol and water (1:1:1, 30mL) was added potassium hydroxide (1.22 g, 21.71 mmol). The reaction wasstirred at 60° C. for 18 h. After completion, the reaction mixture wascooled to room temperature and extracted with 10% methanol indichloromethane (3×50 mL). The combined organic layer was washed withwater, brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude compound was purified bycombiflash column chromatography using 7-8% methanol in dichloromethaneto afford6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(rac-1F) as off white solid. Yield: 555 mg, 69%; MS (ESI) m/z 370.4[M+1]⁺.

The chiral purification of the racemic compound6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 1F) was carried out by SFC chiral HPLC using a Chiralpak-IA(250×21 mm, 5 μm) column using a isocratic mixture of 15%methanol/carbon dioxide. Peak-1: R_(t)=17 min, ee=98.16%; ¹H NMR (400MHz, DMSO-d₆) δ 9.82 (bs, 1H), 8.48 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H),6.50 (s, 2H), 3.33-3.30 (m, 1H), 3.02-2.93 (m, 1H), 2.81-2.79 (m, 1H),2.46-2.45 (m, 1H), 2.44 (s, 3H), 2.21 (s, 3H), 1.98 (s, 3H), 1.93-1.91(m, 2H), 1.72-1.68 (m, 1H), 1.49-1.47 (m, 1H). Peak-2: R_(t)=19.8 min,ee=96.58%; 1H NMR (400 MHz, DMSO-d₆) δ 9.87 (bs, 1H), 8.48 (s, 1H), 8.11(s, 1H), 7.98 (s, 1H), 6.48 (s, 2H), 3.33-3.30 (m, 1H), 2.99-2.93 (m,1H), 2.81-2.79 (m, 1H), 2.49-2.48 (m, 1H), 2.44 (s, 3H), 2.21 (s, 3H),1.98 (s, 3H), 1.93-1.91 (m, 2H), 1.71-1.68 (m, 1H), 1.47 (d, J=12 Hz,1H).

Example 2:(R)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fa) and(S)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fb)

Synthesis of6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dioneHydrochloride (3)

A sealed tube was charged with5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1, 10.0 g,43.2 mmol), tert-butyl 3-oxopiperidine-1-carboxylate (2, 10.31 g, 51.8mmol) and 4 M hydrogen chloride in 1,4-dioxane (100 mL) in 1,4-dioxane(100 mL). The reaction mixture was heated at 110° C. for 16 h. Aftercompletion, the reaction mixture was evaporated under reduced pressureand the solid residue was washed with ether to afford6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dionehydrochloride (3) as light yellow solid. Yield: 20.0 g, 93%; MS (ESI)m/z 312.27[M+1]⁺.

Synthesis of6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(4)

To a solution of6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dionehydrochloride (3, 10.0 g, 28.8 mmol) in N,N-dimethylformamide (75 mL)were added N,N-diisopropylethylamine (9.29 g, 72.04 mmol) and methyliodide (4.50 g, 31.7 mmol) at room temperature. The reaction mixture wasstirred at room temperature for 3 h. Then the reaction mixture wasquenched with ice water and the solid precipitate was isolated byfiltration. The solid was washed with diethyl ether and dried underreduced pressure to afford6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(4) as light brown solid. Yield: 5.3 g, 57%; MS (ESI) m/z 326.2[M+1]⁺.

Synthesis of tert-butyl(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5)

To a solution of6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(4, 15.0 g, 46.1 mmol) in 1,4-dioxane (150 mL) in a sealed tube wereadded tert-butyl carbamate (7.01 g, 59.0 mmol) and cesium carbonate(30.0 g, 92.0 mmol) under argon atmosphere. The reaction mixture waspurged with argon for 15 min followed by the addition of9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.66 g, 4.6 mmol) andtris(dibenzylideneacetone)dipalladium (4.1 g, 4.60 mmol). The mixturewas purged with argon for another 5 min and the reaction mixture washeated at 100° C. for 16 h. After completion, the reaction mass wasconcentrated under vacuum to give the crude compound which was purifiedby silica gel column chromatography (3-5% methanol in dichlorimethane)to afford tert-butyl(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5) as a dark brown solid, which was used for the next step without anyfurther purification. Yield: 9.0 g, 54%; MS (ESI) m/z 363.14[M+1]⁺.

Chiral Separation of tert-butyl(R)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5A) and Tert-butyl(S)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5B)

The racemic compound tert-butyl(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5, 8.0 g) was purified by chiral-SFC using Chiralpak-IG column (250×21mm, 5μm) using an isocratic gradient of 0.2% triethylanime inmethanol/carbon dioxide (40:60). After purification peak-1 was isolatedat R_(t)=8.0 min (2.4 g, ee=99.82%) and peak-2 was isolated atR_(t)=12.8 min (3.4 g, ee=99.60%). Absolute stereochemistry of peak 1and peak-2 were not assigned. For ease of illustration, Peak-1 wasrandomly assigned as tert-butyl(R)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5A) and Peak-2 was randomly assigned as tert-butyl(S)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5B)

Synthesis of(R)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6A)

To a solution of tert-butyl(R)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5A, 2.40 g, 6.6 mmol) in dichloromethane (20 mL) was added 4 M hydrogenchloride in 1,4-dioxane (20 mL). The reaction mixture was stirred atroom temperature for 3 h. After completion, the reaction mass wasconcentrated under vacuum and the crude compound was suspended insaturated solution of sodium bicarbonate. The aqueous layer wasextracted with dichloromethane; the organic layer was dried over sodiumsulphate, filtered and concentrated. The residue was washed with diethylether to give the desired compound(R)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6A) as a light brown solid. Yield: 1.7 g, 98%; MS (ESI) m/z 263.3[M+1]⁺

Synthesis of(R)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fa)

To a solution of(R)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6A, 1.70 g, 6.4 mmol) in tert-butanol (25 mL) were added4-amino-6-chloropyrimidine-5-carbonitrile (7, 1.0 g, 6.4 mmol) andp-toluenesulfonic acid (1.10 g, 6.4 mmol). The reaction mixture washeated at 120° C. for 15 h in a sealed tube. Then the reaction mixturewas concentrated and the residue was dissolved in 20%isopropanol/chloroform (100 mL). The organic layer was washed with asolution of saturated sodium bicarbonate solution, dried over sodiumsulphate, filtered and concentrated. The residue was purified withsilica gel column chromatography using combiflash (5-7% methanol indichloromethane) to afford(R)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fa) as a white solid. Yield: 0.61 g, 25%. MS (ESI) m/z381.13[M+1]⁺; ee=97.94%; Rt=19.96 min, Chiralpak IC (4.6×250 mm, 5μm)using an isocratic gradient of methanol/carbon dioxide (40:60). ¹H NMR(400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.34 (s,1H), 7.79 (bs, 2H), 3.31-3.28 (m, 1H), 2.98-2.94 (m, 1H), 2.82-2.81 (m,1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.99-1.94 (m, 2H), 1.72-1.70 (m, 1H),1.50 (d, J=12.76 Hz, 1H).

Synthesis of(S)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6B)

To a solution of tert-butyl(S)-(1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)carbamate(5B, 3.40 g, 9.3 mmol) in dichloromethane (30 mL) was added 4 M hydrogenchloride in 1,4-dioxane (30 mL). The reaction mixture was stirred atroom temperature for 3 h. After completion, the reaction mass wasconcentrated under vacuum and crude compound was suspended in saturatedsolution of sodium bicarbonate. The aqueous layer was extracted withdichloromethane; the organic layer was dried over sodium sulphate andconcentrated. The residue was washed with diethyl ether to give thedesired compound(S)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6B) as a light brown solid. Yield: 2.1 g, 85%; MS (ESI) m/z263.3[M+1]⁺.

Synthesis of(S)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fb)

To a solution of(S)-6-amino-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(6B, 2.0 g, 7.6 mmol) in tert-butanol (30 mL) were added4-amino-6-chloropyrimidine-5-carbonitrile (7, 1.17 g, 7.6 mmol) andp-toluenesulfonic acid (1.30 g, 7.6 mmol). The reaction mixture washeated at 120° C. for 15 h in a sealed tube. Then the reaction mixturewas concentrated and the residue was dissolved in 20%isopropanol/chloroform (100 mL). The organic layer was washed with asolution of saturated sodium bicarbonate solution, dried over sodiumsulphate, filtered and concentrated. The residue was purified withsilica gel column chromatography using combiflash (5-7% methanol indichloromethane) to afford(S)-4-amino-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 2Fb) as a white solid. Yield: 0.49 g, 18%. MS (ESI) m/z381.17[M+1]⁺; ee=95.58%, Rt=8.89 min, Chiralpak IC (4.6×250 mm, 5μm)using an isocratic gradient of methanol/carbon dioxide (40:60). ¹¹H NMR(400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.34 (s,1H), 7.79 (bs, 2H), 3.29-3.28 (m, 1H), 2.94-2.91 (m, 1H), 2.81-2.80 (m,1H), 2.45 (s, 3H), 2.22 (s, 3H), 1.93-1.88 (m, 2H), 1.72-1.70 (m, 1H),1.49 (d, J=12.76 Hz, 1H).

Example 3

Utilizing appropriate reactants the following compounds can be madeaccording to general methods 1 or 2.

Com- pound No. Structure 3A

3B

3C

3D

rac-1F

3E

3F

3G

3H

3I

3J

3K

3L

3M

3N

3O

3P

3Q

3R

3S

3T

3U

rac-2F

3V

3W

3X

3Y

1Fa

1Fb

2Fa

2Fb

3Z

3AA

3BB

3CC

3DD

3EE

3FF

3GG

3HH

3II

3JJ

3KK

3LL

3MM

3NN

3OO

3PP

3QQ

3RR

3SS

3TT

Example 4:6′-((6-amino-5-chloropyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dioneHydrochloride (Cpd. No. 4A)

Compound 4a can be prepared according to the procedure described inExample 223 of U.S. Pat. No. 9,382,248.

Biological Studies

peIF4E Signaling Cellular Assay

Phosphorylated eIF4E is assayed using the CisBio peIF4E HTRF® assay kit(CisBio, catalogue No. 64EF4PEG). Cells are plated in 96-welltissue-culture treated plate in appropriate growth medium (90 μL).Compounds (10×) are diluted using 3-fold serial dilutions in cellculture medium and added to cells. Plates are incubated for 2 hrs at 37°C. The cell supernatant is carefully removed either by aspiratingsupernatant or by flicking the plate. Immediately 50 μL of supplementedlysis buffer (1×) is added and incubated for at least 30 minutes at roomtemperature under shaking. After homogenization by pipeting up and down,16 μL of cell lysate is transferred from the 96-well cell-culture plateto a 384-well small volume white plate. 4 μL of premixed antibodysolutions (vol/vol) is prepared in the detection buffer and added. Theplate is covered with a plate sealer and incubated overnight at roomtemperature. The fluorescence emissions at two different wavelengths areread (665 nm and 620 nm) on a Wallac Victor2. Emission ratios areconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration of compound necessary to achieve inhibitionof enzyme activity by 50% (IC₅₀) is calculated using concentrationsranging from 20 μM to 0.1 nM (12-point curve). IC₅₀ values aredetermined using a nonlinear regression model available in GraphPadPrism 5.

The results of these assays are set forth in Table 1 below. To this end,IC₅₀ values of less than 0.001 μM are labelled as “+++”, from 0.001 to0.01 μM are labelled as “++”, and greater than 0.01 μM are labelled as“+” (NA means “not available”).

MNK Inhibition Decreases Expression of Immune Checkpoint Receptors andLigands

Upon activation of T cell receptor (TCR) signaling, T cells proliferate,produce cytokines (e.g., IL-2) and induce the expression of immunecheckpoint receptors. Programmed death 1 (PD-1) is an inhibitorycheckpoint receptor expressed on the surface of activated T cells, aswell as on myeloid cells. The ligand for PD-1, programmed death ligand-1(PD-L1, B7-H1/CD274) is not expressed by T cells or normal epithelialcells, but is expressed by antigen presenting cells and overexpressed inseveral cancers. Interaction of PD-1 with PD-L1 results in ananti-proliferative effect on T cells and ultimately T cell exhaustionand apoptosis. To study the role of MNK in activated T cells and tumorcells, the effect of a MNK inhibitor on molecules of immune checkpointcontrol was examined.

PD-1 (CD279) Expression

To examine the effect of MNK inhibitors on PD-1 expression, Jurkat cells(Clone E6.1, ATCC, transformed T cells) were used, which express PD-1when activated through T cell receptor (TCR) signaling. Briefly, Jurkatcells were grown in 1×RPMI with 1×Pen/Strep, and 10% FBS, then about3×10⁶ Jurkat cells were activated in presence of 1 μg/mL PHA (Sigma) and50 ng/mL PMA (Sigma). Test Cells were treated simultaneously withvarious concentrations of an MNK inhibitor (0, 0.01, 0.1, 1, 3 and 10μM). After 48 hours, culture supernatants were harvested and examinedvia sandwich ELISA for the presence of IL-2 using human IL-2 ELISADuoSet (R&D Systems, Minneapolis, Minn.). The level of PD-1 on Jurkatcells was examined by incubating with human FcR block, then contactedwith allophycocyanin (APC) conjugated anti-PD-1 antibody (5 μl per 100μl volume of test, Biolegend, San Diego, CA) for 25 minutes at 4° C.,without washing the cells, fixable dead cell stain (1:10,000; BDBiosciences, San Jose, CA) was added and incubated further for 10minutes at 4° C. Cells were washed two times with flow buffer, andfinally cells were fixed with fixation buffer for 15 minutes at 4° C.After fixation, cells were washed twice with flow buffer andre-suspended in flow buffer and assessed for fluorescence using BDAccuri C6 flow cytometer. Data were analyzed using the C6 cytometersoftware (BD Biosciences, San Jose, CA) or Attune Nxt Cytometer(Invitrogen, Carlsbad, CA).

Activation of Jurkat T cells with PHA and PMA induced the expression ofPD-1 on the cell surface of about 25-30% of the stimulated Jurkat cellsas compared to uninduced cells (Unstim) and induced a 1,000-foldincrease in IL-2 cytokine production, respectively. Treatment of PHA/PMAactivated Jurkat T cells with the MNK inhibitor resulted in aconcentration dependent decrease in the expression of the immuneinhibitory receptor PD-1, up to a 50% reduction at the highestconcentration as compared to control. In addition, this reduction ofPD-1 was not due to a block in Jurkat T cell activation per se since MNKinhibition by an MNK inhibitor did not alter cytokine production asmeasured by IL-2 levels. Lastly, MNK inhibition by various different MNKinhibitors had no effect on cell viability. In fact, various differentMNK inhibitors in the Jurkat T cell assay showed the ability todownregulate immune checkpoint inhibitors without affecting cellviability. The results of these assays are set forth in Table 1 below.To this end, percentage of inhibition of PD-1 positive cells (10 μM) ofmore than 50% are labelled as “+++”, from 10% to 50% are labelled as“++”, and less than 10% are labelled as “+” (NA means “not available”).

Aqueous Solubility

Solubility, the phenomenon of dissolution of solute in solvent to give ahomogenous system, is one of the important parameters to achieve adesired concentration of a compound in systemic circulation for desired(anticipated) pharmacological response. Compounds having good aqueoussolubility are desirable because they result in good in vivobioavailability owing to their high dissolution rate followingadministration to a subject. Compounds having good aqueous solubilityalso contribute to the ease of formulation development, formulationmanufacture and stability of the formulation.

High Throughput Thermodynamic Solubility Procedure

In a 96-well plate, 10 mM DMSO stocks (50-100 uL) of each compound weredried under heated nitrogen flow using a SPE-96 plate dryer (upper flowrate=50 L/min, temperature=60° C., lower flow rate=20 L/min,temperature=80° C.). After DMSO had been completely removed, remainingmaterials were dissolved in test solvents including deionized water,Fasted-State Simulated Intestinal Fluid (FaSSIF, pH 6.5) andFasted-State Simulated Gastric Fluid (FaSSGF, pH 1.6). Compoundsprepared as the free base were assessed in conditions with and withoutone equivalent of TFA added. The theoretical maximum concentrations ofthe aqueous solutions were 10 mM. Each well was capped and incubated fora period of 18 hours at room temperature or 37° C. Mixing of thesolutions during the incubation period was performed by either shakingthe plate at 750 rpm or adding StirStix (stainless steel capillaries)and agitating the mixture using a rotary magnetic tumble stirrer. Afterthe incubation period, aliquots from each well were filtered. Solubilityof all samples were quantified following comparison to standards ofknown concentration by HPLC-UV.

The results of the aqueous solubility are set forth in Table 1 below.

TABLE 1 pEIF4E signaling activity, PD-1 inhibition activity and aqueoussolubility Aqueous pEI4IE PD-1 Solubility Cpd. signaling inhibitionFaSSGF FaSSIF No. activity activity DI H₂O (pH 1.2) (pH 6.5)3-piperidine-substituted compounds 3A + NA 3B + 3C ++ +++ 2.6 4.1 0.2563D ++ 3.3 4.4 0.11 rac-1F ++ ++ 4.3 9.8 0.24 3E + 3F ++ 0.24 0.7 <1 3G++ 3H + 3I +++ 3J ++ 3K + +++ 1.53 1.68 0.158 3L ++ +++ 3.2 3.1 0.07 3M3N ++ 3O +++ 3P +++ 3Q ++ 3R +++ >2.09 0.068 3S ++ +++ 4.2 10 0.6 3T +++ 10 10 0.5 3U + rac-2F ++ ++ 1.84 0.079 3V + 1.82 0.107 3W ++ 1.40.593 3X +++ 3Y +++ 1Fa + ++ >1.85 1.53 0.125 1Fb ++ ++ >1.85 >1.850.088 2Fa ++ ++ 1.84 1.32 0.077 2Fb + ++ 1.77 1.77 0.151 3II 3JJ 3KK 3LL3MM 3NN 3OO 3PP 3QQ 3RR 3SS 3TT Cycloalkyl-substituted compounds 4A ++++++ 0.0003 0.26 0.045 4-piperidine-substituted compounds 3Z ++ 3AA ++ +4.4 3.2 0.03 3BB +++ + 3CC ++ ++ 0.77 1.9 0.04 3DD +++ +++ 2.1 3 0.133EE ++ +++ 3FF +++ ++ 3GG ++ 3.6 3HH ++ + 2.4 0.018

The inventors have unexpectedly found that the dissolution rate of anMnk inhibitor compound can be remarkably improved over comparativecompound 4a by: (i) substituting the imidazopyridine in the compoundwith 3- or 4-piperidine; and (ii) by substituting the pyrimidine in thecompound with lower alkyl, halogen or cyano. Such substitutions orstructural features induce chirality in the molecules.

The improvement in the aqueous solubility of the compounds of theinvention is especially significant in low pH environments, such as ingastric or stomach fluid. For example, as shown in Table 1, compounds3D, 3K, 3L, 3X, 3Y, rac-1F, 1Fa, 1Fb, rac-2F, 2Fa and 2Fb exhibitedexcellent solubility in fasted state simulated gastric fluid (FaSSGF),which has a pH value of 1.6.

Importantly, in addition to improved aqueous solubility, the 3- and4-piperidine-substituted compounds have also retained their anti-cancerpotency in the form of their ability to inhibit pEIF4E signaling. Insome cases, the anti-cancer potency is further manifested in the abilityof these 3- and 4-piperidine-substituted compounds to inhibit PD-1, ascan be seen in Table 1.

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

The invention claimed is:
 1. A method for treating a Mnk dependentcondition in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound having thestructure

or a pharmaceutically acceptable salt thereof, wherein the Mnk dependentcondition is cancer selected from the group consisting of colon cancer,breast cancer, bladder cancer, lung cancer, prostate cancer, cancer ofthe gastrointestinal tract, head and neck cancer, Hodgkin's lymphoma andneuroblastoma.
 2. The method of claim 1, wherein the cancer is selectedfrom non-small cell lung cancer, small cell lung cancer, urothelialcancer, head and neck cancer, and gastric cancer.
 3. The method of claim2, wherein the cancer is non-small cell lung cancer.
 4. The method ofclaim 1, wherein the subject is a mammal.
 5. A method for treating a Mnkdependent condition in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound having the structure

or a pharmaceutically acceptable salt thereof, wherein the Mnk dependentcondition is cancer selected from the group consisting of colon cancer,breast cancer, bladder cancer, lung cancer, prostate cancer, cancer ofthe gastrointestinal tract, head and neck cancer, Hodgkin's lymphoma andneuroblastoma.
 6. The method of claim 5, wherein the cancer is selectedfrom non-small cell lung cancer, small cell lung cancer, urothelialcancer, head and neck cancer, and gastric cancer.
 7. The method of claim6, wherein the cancer is non-small cell lung cancer.
 8. The method ofclaim 5, wherein the subject is a mammal.
 9. A pharmaceuticalcomposition comprising a compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.